JPH0710863B2 - Novel derivative of 4-OH quinolinecarboxylic acid substituted at position 2 with an etherifiable or esterifiable dihydroxy group, a process for its preparation and its use as a medicament - Google Patents

Abstract

Compounds of formula (I): <IMAGE> in which X at 5, 6, 7 or 8 is H, halogen, (C1-5) alkyl, (C1-4) alkoxy, -CF3, -SCF3, -OCF3, R1 is phenyl optionally substituted by at least OH, (C1-5) alkyl, (C1-4) alkoxy, CF3, NO2, halogen or a heterocyclic radical optionally substituted by a (C1-4) alkyl radical, R2 and R3 which are identical or different are H, (C1-4) alkyl, aryl, -C(:O)-R5, R5 being (C1-4) alkyl or aryl. R4 is H, (C1-4) alkyl or aryl, and their addition salts with acids and bases.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention is 4-substituted by a group having two hydroxyl groups at position 2 and may be etherified or esterified.
OH quinolinecarboxylic acid novel derivative, method for producing the same,
And its use as a medicament.

The subject of the invention is the formula (I): [In the formula, X at position 5, 6, 7 or 8 is a hydrogen atom,
Halogen atom, linear or branched alkyl group having 1 to 5 carbon atoms, linear or branched alkoxy group having 1 to 4 carbon atoms, trifluoromethyl group, trifluoromethylthio group Or a trifluoromethoxy group, R ₁ represents a thiazolyl group, R ₂ and R ₃ may be the same or different and each is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an aryl group or —CO— R _{5 represents a} group wherein R ₅ represents an alkyl or aryl group having 1 to 4 carbon atoms, or R ₂ and R ₃ together form an acetonide group and R ₄ is hydrogen. Atom, an alkyl or aryl group having 1 to 4 carbon atoms]
And addition salts of the compounds of formula (I) with acids and bases.

When X represents a halogen atom, it is preferably a chlorine atom.

When X represents an alkyl group, it is preferably one of the following groups: methyl, ethyl, n-propyl, n-.
Butyl, n-pentyl, isopropyl or isobutyl.

When X represents an alkoxy group, this is preferably a methoxy, ethoxy or n-propoxy group.

When R ₂ or R ₃ or R ₄ represents an alkyl group, this is preferably a methyl, ethyl, propyl, isopropyl, butyl or isobutyl group.

When they represent an aryl group, it is preferably a phenyl group.

R ₂ or R ₃ R ₅ is preferably a methyl, ethyl, n-propyl or phenyl group.

Addition salts with acids, such as those formed by mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and also alkyl or aryl sulfonic acids (eg methane sulfonic acid or paratoluene sulfonic acid). Examples thereof include those produced by various sulfonic acids.

Among the addition salts with bases, mention may be made of those formed with alkali metals such as sodium and potassium and amines such as trimethylamine or dimethylamine.

Of particular subject of the invention are compounds in which X is in position 8 and their addition salts with acids and bases, and also compounds in which X represents a trifluoromethyl group, and their addition salts with acids and their bases.

A further subject of the invention is especially the compounds in which X is in position 7 and which represents a chlorine atom, and their addition salts with acids and bases.

More particularly, the subject of the invention is the compounds and acids and bases in which R ₂ and R ₃ represent hydrogen atoms and R ₄ represents a hydrogen atom, an alkyl or aryl group having 1 to 4 carbon atoms. It is the addition salt.

In particular the compounds described in the examples, more particularly: 2- (1,2
-Dihydroxy-ethyl) -4-hydroxy-N- (2
-Thiazolyl) -8-trifluoromethyl-3-quinolinecarboxamide and its addition salts with acids and bases, 2- (1,2-dihydroxy-propyl) -4-hydroxy-N- (2-thiazolyl) -8 -Trifluoromethyl-3-quinolinecarboxamide and its addition salts with acids and bases, 2- [1,2-bis (1-oxopropoxy) -ethyl] -4-hydroxy-N- (2-thiazolyl) -8 -Trifluoromethyl-3-quinolinecarboxamide and its addition salts with acids and bases.

A further subject of the invention is a process for the preparation of compounds having the formula (I), which process comprises the formula (II): [Wherein X and R ₄ have the above-mentioned meanings, and R ′ ₃ is 1 to 4
An alkyl or aryl group having 4 carbon atoms, and X'is a halogen atom].
I _A ): CH ₃ —CONH—R ₁ (III _A ) [wherein R ₁ has the above meaning] and reacted with a compound of formula (IV): Or a compound of formula (III _B ) in the presence of a base: [Wherein R ₁ has the above meaning and R is an alkyl group having 1 to 8 carbon atoms] and is reacted with a compound of formula (A): The compound of formula (IV) above is obtained by dealkoxycarbonylation of the compound of formula (IV) above, and the obtained compound of formula (IV) is cyclized in the presence of an alkali agent to form formula (V): Of the compound of formula (VI): A compound having the formula (VI) is treated with acid hydrolysis to give X, R ₁ and R ₄ in the formula (I) as defined above and R ₂ is a hydrogen atom. And R ₃ is an alkyl group or an aryl group having 1 to 4 carbon atoms, which is optionally used in formula (I) where X, R ₁ , R ₂ and R ₄ have the meanings given above. Yes vital R ₃ is is converted to a compound of a hydrogen atom, then R ₂ and in formula (I) one or both of the hydroxyl groups and etherified or esterified as desired (or) R ₃ is either the same or different It is also possible to obtain a compound having an alkyl group, an aryl group or the above-mentioned —CO—R ₅ group each having 1 to 4 carbon atoms, or, if desired, R ₂ and R ₃ in formula (I) are hydrogen atoms. Treated by treating the indicated compounds with acetone in the presence of acid reagents Or obtain the acetonide, or a-type R ₅ -COOH [R ₅ have the abovementioned meaning] X in formula (I) by treatment with an acid, R ₁ and R ₄ has the abovementioned meaning,
It is desired to obtain a compound in which R ₂ represents a —CO—R ₅ group and R ₃ represents an alkyl or aryl group having 1 to 4 carbon atoms, and a compound of formula (I) thus obtained is desired. Is converted into a salt by the action of an acid or a base.

In preferred conditions for operating the invention, the above process is carried out as follows: X'is a chlorine atom in the compound having formula (II).

The reaction of the compound of formula (II) with the compound of formula (III _A ) is carried out in the presence of an organolithium compound or lithium amide, for example in the presence of butyl-lithium or lithium diisopropylamide.
It is performed at a low temperature of about 70 ° C.

When the compound of formula (II) is reacted with the compound of formula (III _B ) the base used is, for example, sodium hydroxide and the reaction is carried out at room temperature.

This step as well as the operating conditions for the dealkoxycarbonyl of compounds having formula (A) are described in EP 0141
The conditions are the same as those described in Japanese Patent No. 7213.

The cyclization of the compound having formula (IV) is carried out in the presence of an alkaline agent such as hydride or alkali carbonate or amine,
For example, in the presence of: sodium hydroxide, sodium or potassium carbonate, piperidine,
4-aminopyridine, dimethylaminopyridine, triethylamine, 1,5-diazabicyclo [4,3,0] non-5-
Ene, 1,4-diazabicyclo [2,2,2] octane or 1,5
-Diazabicyclo [5,4,0] undec-5-ene.

The cyclization is carried out in the presence of a solvent which is preferably tetrahydrofuran, although other solvents such as dimethylformamide, benzene or toluene can also be used.

Acid hydrolysis of the compound having formula (VI) is preferably carried out with hydrochloric acid, but other acids such as sulfuric acid can also be used.

Conversion of the compound of R ₃ is an alkyl group or an aryl group having from 1 to 4 carbon atoms of formula (I) to the compound of formula (I) wherein R ₃ represents a hydrogen atom, for example, iodide, trimethylsilane or It can be carried out in the presence of boron tribromide.

The operation can be carried out in a solvent such as acetonitrile or methylene chloride.

The etherification or esterification reaction of the compound of formula (I) having one or two hydroxyl groups is carried out by a conventional method.

The acid reagent reacted when forming acetonide is, for example, paratoluenesulfonic acid.

The invention further relates to another process for the preparation of the compounds of formula (I) above, which process comprises the formula (II _A ): Wherein, R ₄ has the meaning given above with a compound of formula _{(III A): CH 3 -CONH} -R 1 (III A) [ In the formula, R ₁ have the abovementioned meaning action of the compound of Over the formula (IV _A ): Of the compound of formula (V _A ): A compound of formula (I) in which X, R ₁ and R ₄ have the meanings given above and R ₂ and R ₃ represent a hydrogen atom, the hydroxyl of this compound having formula (I) One or both groups are optionally etherified or esterified to form an alkyl group, an aryl group or the above-CO-R ₅ in which R ₂ and / or R ₃ has 1 to 4 carbon atoms in the formula (I). A compound of any of the groups, or a compound of formula (I) in which R ₂ and R ₃ represent hydrogen atoms is treated with acetone, optionally in the presence of an acid reagent, to give the corresponding acetonide, which is then required According to the above, the compound having the formula (I) is converted into a salt by the action of an acid or a base.

Conversion of a compound of formula (II _A ) to a compound of formula (IV _A ) and then cyclization to a compound of formula (V _A ) is the same as described above for the first method of the invention. Performed under conditions.

The conversion of the compound of formula (V _A ) to the dihydroxylated compound of formula (I) is preferably carried out in the presence of triethylbenzylammonium chloride by the action of potassium permanganate.

The etherification or esterification of one or both hydroxyl groups of the compound of formula (I) is carried out by conventional methods.

The acid reagent reacted when forming acetonide is, for example, paratoluenesulfonic acid as described above.

The compounds of formula (I) above and their addition salts with acids and bases exhibit valuable pharmacological properties. They have analgesic and anti-inflammatory properties, and they are very active in the case of chronic inflammation.

These properties streamline their therapeutic use, and the subject of the invention is therefore also the compounds of formula (I) as drugs and their pharmaceutically acceptable addition salts with acids and bases.

In particular, the subject of the present invention is the drug 2- (1,2-dihydroxy-ethyl) -4-hydroxy-N- (2-thiazolyl) -8-trifluoromethyl-
3-quinolinecarboxamide and its pharmaceutically acceptable addition salts with acids and bases, 2- (1,2-dihydroxy-propyl) -4-hydroxy-N- (2-thiazolyl) -8-trifluoromethyl-3 -Quinolinecarboxamide and its pharmaceutically acceptable addition salts with acids and bases, 2- [1,2-bis (1-oxopropoxy) -ethyl]
-4-Hydroxy-N- (2-thiazolyl) -8-trifluoromethyl-3-quinolinecarboxamide and its pharmaceutically acceptable addition salts with acids and bases.

The drug which is the subject of the present invention is, for example, treatment of degenerative inflammatory diseases such as osteoarthritis, various collagenosis (tendinitis etc.), rheumatism disease (rheumatoid polyarthritis, ankylosing spondyloarthritis),
And can be recommended for the treatment of other diseases related to autoimmunity such as, for example, disseminated lupus erythematosus, glomerular nephrosis, multiple sclerosis.

Furthermore, the drugs which are the subject of the present invention can also be used for the treatment of muscle pain, neuralgia or arthralgia, toothache, migraine, shingles and the like, as well as adjunctive therapy in infectious and fever states.

The present invention also extends to a pharmaceutical composition containing the above drug as an active ingredient.

These pharmaceutical compositions can be administered by the oral or enteral route, the parenteral route or the topical route for topical application to the skin and mucous membranes.

These compositions may be solid or liquid and are in the pharmaceutical forms currently used in human medicine, such as plain tablets, dragees, capsules, granules, suppositories, injectable preparations, ointments, creams, gels and aerosol preparations. Can be prepared by conventional methods. The active ingredient is an excipient commonly used in these pharmaceutical compositions, for example, talc, arabic gum, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous vehicle, animal or vegetable fatty substance, paraffin derivative. , Glycols, various wetting agents, dispersants or emulsifiers, and preservatives.

The particular dosage will depend on the route of administration, the condition being treated and the patient involved.

For example, in adults, the active ingredient may be taken daily by the oral route.
It can vary in the range of 20mg / 2g.

The compounds having the formulas (II) and (II _A ) can be produced by the method described in European Patent No. 40573.

Formulas (II), (II _A ), (IV), (IV _A ), (V),
The compounds having ( _VA ), (A), and (VI) are novel compounds.

Hereinafter, the present invention will be described with reference to examples, but the present invention is not limited thereto.

Example 1: 4-hydroxy-2- (1-hydroxy-2
-Methoxy-ethyl) -N- (2-thiazolyl) -8-
(Trifluoromethyl) -3-quinolinecarboxamide Step A: 2-[(2-chloro-3-methoxy-1-oxopropyl) amino] β-oxo-N- (2-thiazolyl) -3-trifluoromethyl Benzenepropanamide.

350m of a solution of n-butyllithium in hexane at 0 ° C
1 of 1 was introduced into a suspension of 34 g of 2-acetylaminothiazole in 1100 ml of tetrahydrofuran. This was cooled to -70 / 75 ° C and then added to 2-
(1-Chloro-2-methoxyethyl) -8-trifluoromethyl-4-H-3,1-benzoxazin-4-one [2-chloro-3-methoxypropanoic acid (Chemical Berichte, vol. 92, 1081) -7 pages (1959) and 2-amino-
Starting from 3-trifluoromethylbenzoic acid, a solution of 36.78 g of the compound prepared analogously to step A in example 12 of EP 40573] was added.

The resulting solution was poured into an aqueous solution of hydrochloric acid and extracted with ether. The extract was washed with N hydrochloric acid and then water, dried and concentrated under reduced pressure.

The residue was tritylated in ether, separated, washed with ether and dried under reduced pressure to give 33.35 g of the expected product. Melting point 190 ° C.

Analysis: C ₁₇ H ₁₅ N ₃ O ₄ F ₃ SCl: 449.845 C% H% N% F% Cl% S% Calculated value: 45.39 3.36 9.34 12.67 7.88 7.13 Found value: 45.6 3.4 9.0 12.4 7.8 7.1 Process B: 2- (1-Chloro-2-methoxyethyl) -4-
Hydroxy N- (2-thiazolyl) -8-trifluoromethyl-3-quinolinecarboxamide.

33.35 g of the product from step A and 10 dimethylaminopyridine
g and were heated in 300 ml of tetrahydrofuran under reflux for 30 minutes.

After cooling to room temperature, it was poured into a mixture of water and 2N hydrochloric acid and extracted with ethyl acetate. Wash the extract,
It was dried and concentrated under reduced pressure. The residue was tritylated in ether, then separated, washed and dried at 60 ° C. under reduced pressure to give 28.2 g of the expected product. Melting point 186 ° C.

Step C: 1,3-dihydro-3- (methoxymethyl) -1-
[(2-thiazolyl) -imino] -5-trifluoromethylfuro [3,4, b] quinolin-9-ol.

23.9 g of product from Step B and potassium t-butyrate 7.7
g and were refluxed in 550 ml of dioxane for 30 minutes. Dioxane was removed under reduced pressure, the residue was dissolved in a mixture of water and 2N hydrochloric acid, and the insoluble material was extracted with a mixture of ethyl acetate and tetrahydrofuran (80/20). The organic phases were washed with water and the aqueous phases were combined.

The aqueous phase was neutralized by adding saturated aqueous sodium bicarbonate solution and then extracted with ethyl acetate. The extract was washed with water, dried and concentrated under reduced pressure. 22 g of the expected product was obtained.

Step D: 4-Hydroxy-2- (1-hydroxy-2-methoxyethyl) -N- (2-thiazolyl) -8- (trifluoromethyl) -3-quinolinecarboxamide.

A solution containing 22 g of the product from step C, 70 ml of water and 130 ml of concentrated hydrochloric acid was stirred at room temperature for 16 hours.

The precipitate formed was separated off, washed with water, then dissolved in 200 ml of water and extracted with a mixture of ethyl acetate and tetrahydrofuran (50/50). The organic phase was washed with water, dried and concentrated under reduced pressure to give 15 g of product, which was purified by chromatography on silica under pressure (eluent: ethyl acetate). 12.5 g of product were obtained, which was tritylated in ether, separated, washed with ether and dried under reduced pressure at 100 ° C.

11.83 g of the expected product are obtained, which melts at 216-218 ° C.

Analysis: C ₁₇ H ₁₄ O ₄ N ₃ F ₃ S: 413.384 C% H% N% F% S% Calculated value: 49.39 3.41 10.16 13.76 7.76 Measured value: 49.5 3.4 10.2 13.9. 7.7 Example 2: 2- (1 , 2-Dihydroxyethyl) -4-hydroxy-N- (2-thiazolyl) -8-trifluoromethyl-3-quinolinecarboxamide Under an inert atmosphere, 6.7 ml of iodinated trimethylsilane was added from Example 1. 6.5 g of product and 120 ml of acetonitrile
It was slowly introduced into the mixture containing and. 16 at room temperature
After stirring for an hour, the mixture was poured into 400 ml of water and to this was added 50 ml of sodium bisulfate.

The obtained suspension was stirred at room temperature for 45 minutes, 100 ml of ethyl ether was added, and the mixture was further stirred for 30 minutes. After separation, washing with water and drying at 75 ° C. under reduced pressure for 16 hours, 5.9 g of product are obtained, which is dissolved in 75 ml of dimethylformamide and then filtered. Ether was added to the filtrate and then cooled, the crystals obtained were separated, washed with ether and dried at 120 ° C. under reduced pressure. 4.86 g of the expected product are obtained, which melts at 225 ° C.

Analysis: C ₁₆ H ₁₂ N ₃ F ₃ O ₄ S: 399.356 C% H% N% F% S% Calculated value: 48.12 3.03 10.52 14.27 8.03 Measured value: 48.0 3.0 10.4 14.1 8.0 Example 3: 2- (1, 2-Dihydroxypropyl) -4-hydroxy-N- (2-thiazolyl) -8-trifluoromethyl-3-quinolinecarboxamide Step A: β-oxo-2-[(1-oxo-2-butenyl) -amino ] -N- (2-thiazolyl) -3-trifluoromethylbenzenepropanamide.

19.44 g of 2-acetylaminothiazole and 17.3 g of 2-
(1-Propenyl) -8-trifluoromethyl-4-H
The procedure is the same as in step A of example 1, starting with -3,1-benzoxazin-4-one. This compound is 2
Example 12 of EP 40,573 starting from -amino-trifluoromethylbenzoic acid and crotonyl chloride.
It was created in the same manner as in step A of.

19.03 g of the expected product are obtained, which melts at 206-208.degree.

Step B: 4-hydroxy-2- (1-propenyl) -N-
(2-thiazolyl) -8-trifluoromethyl-3-quinolinecarboxamide.

Product from Step A in 175 ml of dimethylacetamide 1
7.5 g of the solution was added to a mixture containing 2.11 g of sodium hydride and 100 ml of dimethylacetamide dispersed at 50% in oil. The whole was heated to 120 ° C. and kept at this temperature for 30 minutes.

The solution was cooled and then poured into a mixture of water and 2N hydrochloric acid. The precipitate obtained was separated, washed with water and dried at 80 ° C. under reduced pressure to give 16.7 g of the expected product. This is 265
Melt at ℃.

Step C: 2- (1,2-dihydroxypropyl) -4-hydroxy-N- (2-thiazolyl) -8-trifluoromethyl-3-quinolinecarboxamide.

A mixture containing 12.2 g of the product from Step B, 9.16 g of methylbenzylammonium chloride and 6.32 g of potassium permanganate in 300 ml of methylene chloride was stirred at 0 ° C. for 1 hour.

150 ml of water and then 150 ml of a solution of sodium bisulfite were added. The insoluble material obtained was separated, washed with water and partially dissolved in tetrahydrofuran.

The organic solution was dried and concentrated under reduced pressure to give 5.8 g of crude product, which was dissolved in warm dimethylformamide. The resulting solution is filtered and concentrated to about 40 ml, then 60 ml
Of ethyl ether was added. After cooling, the crystals obtained were separated, washed with ether, dried under reduced pressure at 100 ° C. and the product obtained was dissolved in tetrahydrofuran.

The solution was filtered, concentrated under reduced pressure and the residue tritylated in ethyl acetate, then separated, washed and dried under reduced pressure at 100 ° C. to give 3.04 g of the desired product. It melts at 275 ° C.

Analysis: C ₁₇ H ₁₄ N ₃ O ₄ F ₃ S: 413.384 C% H% N% F% S% Calculated value: 49.39 3.41 10.16 13.79 7.76 Measured value: 49.3 3.3 10.1 14.1 7.8 Example 4: 2- [1, 2-bis (1-oxopropoxy) ethyl] -4-hydroxy-N- (2-thiazolyl) -8
-Trifluoromethyl-3-quinolinecarboxamide At 20 ° C, 2.15 g of the product obtained in Example 2, 70 ml of methylene chloride and 0.96 ml of propionic acid were mixed. After 5 minutes, 2.9 g of dicyclohexyldicarbodiimide and then 2.4 g of dimethylaminopyridine were added, the whole was kept under stirring for 1.5 hours and then filtered. The filtrate was washed with a saturated aqueous solution of sodium carbonate, an aqueous solution of hydrochloric acid, and then water. The residue after drying and evaporation to dryness was recrystallized from acetonitrile. 1.34 g of the expected product was obtained. Melting point 206 ° C.

Analysis: C ₂₂ H ₂₀ F ₃ N ₃ O ₆ S: 511.179 C% H% N% S% F% Calculated value: 51.66 3.94 8.22 6.27 11.14 Measured value: 51.7 3.9 8.1 6.2 11.1 Example 5: 2- [2- Methoxy-1- (1-oxopropoxy) ethyl] -4-hydroxy-N- (2-thiazolyl) -8-trifluoromethyl-3-quinolinecarboxamide 2 g of the product obtained in Example 1 at the start and propionic acid 0.4 ml
Using 1.2 g of dicyclohexylcarbodiimide and 0.3 g of dimethylaminopyridine, a procedure similar to that described in Example 4 was performed. After recrystallisation from ethyl acetate, 1 g of the expected product was obtained. mp = 190 ° C.

Analysis: C ₂₀ H ₁₈ F ₃ N ₃ O ₅ S: 469.442 C% H% F% N% S% Calculated value: 51.17 3.87 12.14 8.95 6.83 Measured value: 51.5 4.0 11.9 8.9 6.5 Example 6: 2- [1, 2 (dibenzoyloxy) ethyl]-
4-Hydroxy-N- (2-thiazolyl) -8-trifluoromethyl-3-quinolinecarboxamide 0.5 g of the product obtained in Example 2 at the start and 0.37 benzoic acid
An operation was carried out in the same manner as described in Example 4, using g, 0.67 g of dicyclohexylcarbodiimide and 0.075 g of dimethylaminopyridine. 0.8 g of crude product was obtained, which was dissolved in 15 ml of tetrahydrofuran and to this was added 0.3 ml of 5.7N hydrochloric acid solution in ethanol. The crystals formed were separated, dissolved in a mixture of ethyl acetate and water, then extracted with ethyl acetate, dried and concentrated to dryness. The residue was dissolved in tetrahydrofuran, ethyl ether was added, then cooled to 0 ° C. for 2 hours. The crystals were separated and dried to give 0.33g of the desired product. mp = 240 ° C.

Analysis: C ₃₀ H ₂₀ F ₃ N ₃ O ₆ S: 607.658 C% H% N% F% S% Calculated value: 59.31 3.32 6.91 9.38 5.28 Measured value: 59.2 3.2 6.9 9.6 5.4 Example 7: 2- [1, 2 (diacetyloxy) ethyl] -4
-Hydroxy-N- (2-thiazolyl) -8-trifluoromethyl-3-quinolinecarboxamide 2 g of the product obtained in Example 2 at the start, 0.7 ml of acetic acid, 2.7 g of dicyclohexylcarbodiimide and 0.3 g of dimethylaminopyridine were added. Was carried out as described in Example 4. 0.9 g of crude product is obtained, which contains a small amount of dicyclohexylurea, which is washed with tetrahydrofuran, recrystallized from dimethylformamide,
It was then removed by formation of the hydrochloride salt in tetrahydrofuran, to which was added a solution of hydrochloric acid in ethanol. After recrystallisation from acetic acid, 0.38 g of the expected product was obtained. mp = 270 ° C.

Analysis: C ₂₀ H ₁₆ F ₃ N ₃ O ₆ S: 483.432 C% H% N% F% S% Calculated value: 49.69 3.34 8.69 11.79 6.63 Measured value: 49.4 3.2 8.4 11.9 6.8 Example 8: 2- (2, 2-dimethyl-1,3-dioxolane-
4-yl) -4-hydroxy-N- (2-thiazolyl)
-8-Trifluoromethyl-3-quinolinecarboxamide 3 g of the product obtained in Example 2 were suspended in 80 ml of acetone and refluxed. 0.3 g of paratoluenesulfonic acid was added and the whole was refluxed for 5 hours. After cooling to 20 ° C,
The crystals formed were separated, dried under reduced pressure and then dissolved in 100 ml of tetrahydrofuran by warming them to 40 ° C. Filter, concentrate to half volume, and
After cooling to ° C and adding ethyl ether, the crystals were separated, washed with ethyl ether and dried. 1.2 g of the expected product was obtained. mp = 250 ° C.

Analysis: C ₁₉ H ₁₆ F ₃ N ₃ O ₄ S: 439.417 C% H% N% F% S% Calculated: 51.94 3.67 9.56 12.97 7.30 Found: 51.8 3.5 9.4 12.8 7.1 Example 9: 4-Hydroxy-2 -(1-hydroxy-2
-Methoxyethyl) -N- (2-thiazolyl) -7-chloro-3-quinolinecarboxamide Step A: 2-[(2-chloro-3-methoxy-1-oxopropyl) amino] β-oxo-N- (2-thiazolyl) -4-chlorobenzenepropanamide.

2- (1-chloro-2-methoxyethyl) -7 on departure
-Chloro-4H-3,1-benzoxazin-4-one [2-
Chlor-3-methoxypropanoic acid and 2-amino-4-
Starting from chlorobenzoic acid, European patent application No. 4057
Compound No. 3, mp 82 ° C., prepared as described in Example 12, Step A, was used and operated in the same manner as described in Example 1, Step A. The desired product, melting at 180 ° C., was obtained in a yield of 76%.

Step B: 2- (1-Chloro-2-methoxyethyl) -4-
Hydroxy-N- (2-thiazolyl) -7-chloro-3
-Quinoline carboxamide.

Operation was carried out in the same manner as described in Example 1, step B. This product was used in the next step without isolation.

Step C: 1,3-dihydro-3- (methoxymethyl) -1-
[(2-thiazolyl) imino] -6-chlorfuro] -3,
4-b [quinolin-9-ol].

The procedure was the same as described in Step C of Example 1, except that the quinoline of Step D above was not intermediately isolated and was run under reflux of tetrahydrofuran for 24 hours. The desired product was obtained in a yield of 65%. mp> 270
° C.

Step D: 4-Hydroxy-2- (1-hydroxy-2-methoxyethyl) -N- (2-thiazolyl) -7-chloro-3-quinolinecarboxamide.

Perform the same operation as described in Step D of Example 1 to give 6N
It was kept under stirring in hydrochloric acid for 37 hours. The desired product was obtained. mp> 270 ° C.

Example 10: 2- (1,2-Dihydroxyethyl) -4-hydroxy-N- (2-thiazolyl) -7-chloro-3-
Example of pharmaceutical composition of quinolinecarboxamide: Example 11: A tablet corresponding to the following formulation was prepared: Compound of Example 2 ... 50 mg A sufficient amount of excipient for a tablet to be finished to the right amount ... 350 mg (shaping) Details of the drug: Lactose, talc, amidone, magnesium stearate) Pharmacological study Anti-inflammatory activity: Adjuvant chronic arthritis (preventive treatment) Injection of Freund's ajobite in the rat's hindpaw rapidly induces primary inflammatory lesions in this foot , Then 13
After an incubation period of ~ 15 days, secondary arthritis developed, affecting especially the other hindpaw. This test was performed on male rats aged 42 to 50 days, and these rats were planted with 0.1 ml of "Freund" type adjuvant (6 mg of killed suspension of Mycobacterium butyricum in vaseline oil per ml). Injected inside.

Day 0 (the day of adjuvant injection) for these animals
To the day before these animals died (occurring on day 17) the test compound was administered by the oral route. Comparative arthritic and normal comparative animals received vehicle only. The evaluation criteria for the activity of the substances studied are the increase in the volume of the injected hindpaw (primary and secondary inflammation) and the increase in the absence of the injection (secondary inflammation), compared to the corresponding mean volume of the foot. To do.

The DA ₅₀ was measured, ie the dose that reduced the volume increase in the hindpaw of the treated animals by 50% compared to the control animals. The measured DA ₅₀ is the compound of Examples 1, 2, 3, 4, and 5. About 2mg / kg, 0.7mg / kg, 3mg / kg, 1mg / kg
And was 5 mg / kg.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Office reference number FI technical display location // C07D 215/56

Claims (10)

[Claims] 1. Formula (I): [In the formula, X at position 5, 6, 7 or 8 is a hydrogen atom,
Halogen atom, linear or branched alkyl group having 1 to 5 carbon atoms, linear or branched alkoxy group having 1 to 4 carbon atoms, trifluoromethyl group, trifluoromethylthio group Or a trifluoromethoxy group, R ₁ represents a thiazolyl group, R ₂ and R ₃ may be the same or different, each a hydrogen atom,
An alkyl group having 1 to 4 carbon atoms, an aryl group or a —CO—R ₅ group (wherein R ₅ represents an alkyl group having 1 to 4 carbon atoms or an aryl group) or R ₂ And R ₃ together form an acetonide group, R ₄ represents a hydrogen atom, an alkyl group or an aryl group having 1 to 4 carbon atoms], and a compound of formula (I) with an acid and a base. Addition salts of the compounds of. 2. Claim 1 in which X is at position 8.
A compound having the formula (I) as described in the above item, and addition salts thereof with acids and bases. 3. A compound having the formula (I) according to claim 1 or 2, wherein X represents a trifluoromethyl group, and addition salts thereof with an acid and a base. 4. Claim 1 in which X is at position 7.
A compound having the formula (I) as described in the above item, and addition salts thereof with acids and bases. 5. A compound having the formula (I) according to claim 1 or 4, wherein X represents a chlorine atom, and addition salts thereof with acids and bases. 6. A method according to claim 1, wherein R ₂ and R ₃ represent a hydrogen atom, and R ₄ represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms or an aryl group. A compound of any of the formulas (I), and addition salts thereof with acids and bases. 7. 2- (1,2-Dihydroxy-ethyl) -4
-Hydroxy-N- (2-thiazolyl) -8-trifluoromethyl-3-quinolinecarboxamide and its addition salts with acids and bases, 2- (1,2-dihydroxy-propyl) -4-hydroxy-N- (2-thiazolyl) -8-trifluoromethyl-3-quinolinecarboxamide, and its addition salts with acids and bases, 2- [1,2-bis (1-oxopropoxy) -ethyl]
-4-Hydroxy-N- (2-thiazolyl) -8-trifluoromethyl-3-quinolinecarboxamide, and its addition salts with acids and bases having formula (I) according to claim 1. Compounds and their addition salts with acids and bases. 8. Formula (I): [In the formula, X at position 5, 6, 7 or 8 is a hydrogen atom,
Halogen atom, linear or branched alkyl group having 1 to 5 carbon atoms, linear or branched alkoxy group having 1 to 4 carbon atoms, trifluoromethyl group, trifluoromethylthio group Or a trifluoromethoxy group, R ₁ represents a thiazolyl group, R ₂ and R ₃ may be the same or different, each a hydrogen atom,
An alkyl group having 1 to 4 carbon atoms, an aryl group or a —CO—R ₅ group (wherein R ₅ represents an alkyl group having 1 to 4 carbon atoms or an aryl group) or R ₂ And R ₃ together form an acetonide group, R ₄ represents a hydrogen atom, an alkyl group or an aryl group having 1 to 4 carbon atoms], and a compound of formula (I) with an acid and a base. A method for producing an addition salt of a compound of formula (II): [Wherein X and R ₄ have the above-mentioned meanings, and R ′ ₃ is 1 to 4
A compound of formula (III _A ): CH ₃ -CONHR ₁ (III _A ), wherein R ₁ is an alkyl or aryl group having 4 carbon atoms and X ′ is a halogen atom. Meaning] is reacted with a compound of formula (IV): Or in the presence of a base of formula (III _B ): [Wherein R ₁ has the above meaning and R is an alkyl group having 1 to 8 carbon atoms] and is reacted with a compound of formula (A): The compound of formula (IV) is obtained by dealkoxycarbonylating the compound of formula (IV) above, and the obtained compound of formula (IV) is cyclized in the presence of an alkaline agent to give formula (V): Of the compound of formula (VI): A compound having the formula (VI) is treated by acid hydrolysis to give X, R ₁ and R ₄ in the formula (I) as defined above and R ₂ is a hydrogen atom. And R ₃ is an alkyl group or an aryl group having 1 to 4 carbon atoms, which is optionally used in formula (I) where X, R ₁ , R ₂ and R ₄ have the meanings given above. Yes vital R ₃ is is converted to a compound of a hydrogen atom, then R ₂ and in formula (I) one or both of the hydroxyl groups and etherified or esterified as desired (or) R ₃ is either the same or different It is also possible to obtain a compound having an alkyl group, an aryl group or the above-mentioned —CO—R ₅ group each having 1 to 4 carbon atoms, or, if desired, R ₂ and R ₃ in formula (I) each represent a hydrogen atom. Treated by treating the indicated compounds with acetone in the presence of acid reagents Or an acetonide of the formula: or treatment with an acid of formula R ₅ —COOH [R ₅ has the meanings given above], wherein X, R ₁ and R ₄ in formula (I) have the meanings given above,
It is desired to obtain a compound in which R ₂ represents a —CO—R ₅ group and R ₃ represents an alkyl or aryl group having 1 to 4 carbon atoms, and a compound of formula (I) thus obtained is desired. The method is characterized in that it is converted into a salt by the action of an acid or a base according to the above. 9. Formula (I): [In the formula, X at position 5, 6, 7 or 8 is a hydrogen atom,
Halogen atom, linear or branched alkyl group having 1 to 5 carbon atoms, linear or branched alkoxy group having 1 to 4 carbon atoms, trifluoromethyl group, trifluoromethylthio group Or a trifluoromethoxy group, R ₁ represents a thiazolyl group, R ₂ and R ₃ may be the same or different, each a hydrogen atom,
An alkyl group having 1 to 4 carbon atoms, an aryl group or a —CO—R ₅ group (wherein R ₅ represents an alkyl group having 1 to 4 carbon atoms or an aryl group) or R ₂ And R ₃ together form an acetonide group, R ₄ represents a hydrogen atom, an alkyl group or an aryl group having 1 to 4 carbon atoms], and a compound of formula (I) with an acid and a base. A method for producing an addition salt of a compound of formula (II _A ): Wherein, R ₄ has the meaning given above with a compound of formula _{(III A): CH 3 -CONH} -R 1 (III A) [ In the formula, R ₁ have the abovementioned meaning action of the compound of Let Expression (IV _A ): Of the compound of formula (V _A ): A compound of formula (I) in which X, R ₁ and R ₄ have the meanings given above and R ₂ and R ₃ represent hydrogen atoms in formula (I) One or both of the hydroxyl groups of the above are optionally etherified or esterified to form an alkyl group, an aryl group or -CO-R in which R ₂ and / or R ₃ in the formula (I) has 1 to 4 carbon atoms. ₅ compounds (wherein R ₅ has the meanings given above) are obtained, or compounds of the formula (I) in which R ₂ and R ₃ represent hydrogen atoms are optionally prepared in the presence of an acid reagent. Process as described above, characterized by treatment with acetone to give the corresponding acetonide, and then optionally converting the compound of formula (I) into a salt by the action of an acid or base. 10. Formula (I): [In the formula, X at position 5, 6, 7 or 8 is a hydrogen atom,
Halogen atom, linear or branched alkyl group having 1 to 5 carbon atoms, linear or branched alkoxy group having 1 to 4 carbon atoms, trifluoromethyl group, trifluoromethylthio group Or a trifluoromethoxy group, R ₁ represents a thiazolyl group, R ₂ and R ₃ may be the same or different, each a hydrogen atom,
An alkyl group having 1 to 4 carbon atoms, an aryl group or a —CO—R ₅ group (wherein R ₅ represents an alkyl group having 1 to 4 carbon atoms or an aryl group) or R ₂ And R ₃ together form an acetonide group, R ₄ represents a hydrogen atom, an alkyl group or an aryl group having 1 to 4 carbon atoms], and a compound of formula (I) with an acid and a base. An anti-inflammatory agent containing as an active ingredient at least one addition salt of the compound of the above.